2- OR 3-Phenyl 1,4-disubstituted phenyl piperazines

ABSTRACT

Novel 1,4-substituted phenyl piperazine compounds have a pronounced effect upon blood coagulation and are useful in the treatment of thrombotic diseases, especially of the arterial system. They are particularly used to inhibit thrombosis of the coronary or cerebral arteries. Examples of such compounds are 1-phenyl (lower) alkyl-2-phenyl-4-di-(lower)alkylamino (lower)alkyl piperazines, 1-phenyl (lower)alkyl-3-phenyl-4-di-(lower)alkylamino (lower)alkyl piperazines and their pharmaceutically acceptable acid addition salts. The phenyl ring in 1-position may be substituted by halogen, trifluoro (lower)alkyl, lower alkoxy, or phenyl lower alkoxy; the di-(lower)alkylamino (lower)alkyl group in 4-position may be replaced by piperidino (lower)akyl, morpholino (lower)alkyl, pyrrolidino (lower)alkyl, piperazino (lower)alkyl, or the like mononuclear nitrogen-containing heterocyclically substituted (lower)alkyl.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a division of copending Application Ser. No.333,497, filed Feb. 20, 1973, now U.S. Pat. No. 3,935,214; issued Jan.27, 1976, and entitled 2- OR 3-KETO-C-PHENYL-1,4-DISUBSTITUTEDPIPERAZINES, said application Ser. No. 333,497 in turn being acontinuation-in-part application of copending Application Ser. No.848,395, filed July 23, 1969, and entitled 1,4-DISUBSTITUTED PHENYLPIPERAZINE COMPOUNDS, COMPOSITIONS CONTAINING SAME, AND PROCESS OFMAKING AND USING SAME, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to new and valuable phenyl piperazinecompounds and more particularly to 1,4-substituted phenyl piperazinecompounds of noteworthy therapeutic utility and to a process of makingand using same.

2. Description of the Prior Art

ARCHER in U.S. Pat. No. 3,062,821 discloses1,4-disubstituted-2-piperazinones of Formula I ##STR1## In said formulaR represents lower alkyl;

X and X' represent hydrogen, lower alkoxy, or hydroxyl; and

Y hydrogen or lower alkyl.

Said 1-[2-(phenyl lower alkyl)]-4-lower alkyl-2-piperazinone compoundsare useful intermediates in the preparation of compounds of Formula II##STR2## in which R, X, X', and Y represent the same substituents asgiven hereinabove. These 1-[2-(phenyl lower alkyl)]-4-lower alkylpiperazine compounds are useful hypotensive agents.

DE BENNEVILLE in U.S. Pat. No. 3,390,139 disclosesN-vinyl-2-piperazinones of Formula III ##STR3## in which R₁ is hydrogen,alkyl, cycloalkyl, aralkyl, alkyl substituted aralkyl, diaminoalkyl, orfurfuryl;

R₂ is hydrogen or methyl;

R₃ is hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, alkyl, chloro, oralkoxy substituted phenyl or naphthyl, aralkyl, alkyl substitutedaralkyl, or 2-furyl;

R₄ is hydrogen or alkyl; and

R₅ is hydrogen or alkyl.

These compounds are polymerizable or copolymerizable compounds, theresulting polymers or copolymers are useful for many purposes. Highermembers of the monomeric N-vinyl-2-piperazinones of Formula III showfungistatic and bacteriostatic activity and are useful for otherpurposes.

DE BENNEVILLE in U.S. Pat. No. 2,653,153 describes4-N-substituted-2-ketopiperazines of Formula IV ##STR4## in which R isalkyl, tertiary aminoalkyl, or aralkyl; and

R' and R" are hydrogen or lower alkyl. These4-N-substituted-2-ketopiperazines are valuable activators and synergistsfor insecticidal agents.

None of these compounds has found any noteworthy application inveterinary and human therapy.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide valuable1,4-substituted phenyl piperazine compounds which have a surprising andpronounced effect upon blood coagulation and are useful, for instance,in the treatment of thrombotic diseases, especially those of thearterial system.

Another object of the present invention is to provide a simple andeffective process of producing such valuable novel 1,4-substitutedphenyl piperazine compounds.

A further object of the present invention is to provide pharmaceuticalcompositions containing, as active pharmaceutical agent, said novel1,4-substituted phenyl piperazine compounds

Still another object of the present invention is to provide a method oftherapeutically affecting blood coagulation by administering the novel1,4-substituted phenyl piperazine compounds.

Other objects of the present invention and advantageous features thereofwill become apparent as the description proceeds.

In principle, the new 1,4-substituted phenyl piperazine compoundsaccording to the present invention correspond to the following formula V##STR5## In said formula X, Y, and Z are the same or differentsubstituents and may be either hydrogen, halogen, trifluoro lower alkyl,preferably trifluoro methyl, hydroxyl, lower alkoxy, preferably methoxyor ethoxy, or phenyl substituted lower alkoxy, such as benzyloxy;

R is di-(lower)alkylamino (lower)alkyl, and preferably dimethylaminoethyl, diethylamino ethyl, dipropylamino ethyl, dimethylamino propyl,diethylamino propyl, di-n-propylamino propyl, or lower alkyl substitutedby one or two saturated monocyclic heterocyclic rings such aspiperidino, pyrrolidino, piperazino, N-lower alkyl piperazino,3-ketopiperazino, morpholino, or the like, preferably piperidino ethyl,morpholino ethyl, or dimorpholino propyl;

R₁ is lower alkyl with 1 to 3 carbon atoms; and ##STR6## is the group##STR7##

The term "lower alkyl" in said substituents indicates alkyl with 1 to 5carbon atoms. Thus the substituent in N₁ -position of the piperazinering may be benzyl, phenyl ethyl, or phenyl propyl, or substitutedbenzyl, phenyl ethyl, phenyl propyl. Preferred substituents in the N₁-aralkyl group are

One halogen atom in 2-; 3-; or 4-position.

Two halogen atoms in 2,3-; 2,4-; 2,5-; or 3,4- position and, if desired,also in 2,6-position.

Such halogen substituted compounds may also carry hydroxyl or loweralkoxy, preferably methoxy groups.

One lower alkoxy group, preferably one methoxy or ethoxy group in4-position.

Three lower alkoxy groups, preferably in 3,4,5-position.

One phenyl lower alkoxy group, preferably the benzyloxy group in 2- or4-position.

Two phenyl lower alkoxy groups, preferably the benzyloxy groups in3,4-position.

Two hydroxyl groups, preferably in 2,3, and/or 4-position.

One trifluoro lower alkyl group, preferably the trifluoromethyl group in3-position. addition

The phenyl radical in position 2 or 3 of the piperazine ring is alwaysunsubstituted.

The basic lower alkylamino group in N₄ -position is preferably a groupof the Formula VI ##STR8## in which R₂ is lower alkyl;

R₃ is hydrogen or a saturated five- or six-membered heterocyclic ring,preferably the morpholino ring attached by its heterocyclic nitrogenatom to the lower alkyl R₂ ; and

R₄ and R₅ are lower alkyl or, together with the nitrogen atom to whichthey are attached, form a saturated five- or six-membered heterocyclicring, such as the pyrrolidino, piperidino, piperazino, or morpholinoring. The piperazino ring may be substituted at its other nitrogen atomby lower alkyl or by hydroxy lower alkyl to represent the N₄ -loweralkyl or N₄ -hydroxy lower alkyl piperazino ring or it may besubstituted by a keto group to represent the 3-keto piperazino ring.

It is evident that the compounds according to the present inventionrepresent two groups of compounds, namely

a. The N₁ -phenyl lower alkyl substituted 2- or 3-phenyl substituted N₄-basically substituted 3- or 2-piperazone compounds of Formulas VII orVIII: ##STR9## and b. the N₁ -phenyl lower alkyl substituted 2- or3-phenyl substituted N₄ -basically substituted piperazine compounds ofFormulas IX and X: ##STR10##

In said Formulas VII to X the symbols R₁, R₂, R₃, R₄, R₅, X, Y, and Zrepresent the same substituents as indicated hereinabove.

Especially valuable compounds according to the present invention arecompounds of the following Formula XI and XII: ##STR11## In saidFormulas X₁ is hydrogen or lower alkoxy.

Y₁ and Z₁ are hydrogen, halogen, trifluoromethyl; hydroxyl, loweralkoxy, and phenyl lower alkoxy, whereby X₁ is lower alkoxy only if Y₁and Z₁ are lower alkoxy;

R₁ is lower alkyl with 1 to 3 carbon atoms;

R₂ is lower alkyl;

R₃ is hydrogen or a saturated five- or six-membered heterocyclic ring,said heterocyclic ring being attached by its heterocyclic nitrogen atomto the lower alkyl R₂ ;

R₄ and R₅ are lower alkyl or, together with the nitrogen atom to whichthey are attached, form a saturated five- or six-membered heterocyclicring.

According to the present invention the 1,4-substituted phenyl piperazinecompounds of the above given Formulas have a pronounced effect upon theblood coagulation system. They act upon all processes which play anessential role in the formation of thromboses, such as their coagulationpromoting effect due to their power of releasing the thrombocyte factor3, their coagulation inhibiting effect, and their trombocytesaggregation and adhesion inhibiting effect. Thus the novel compounds ofthe present invention or their pharmaceutically acceptable acid additionsalts are highly effective anticoagulants. They prolong the clottingtime of blood on oral or parenteral administration of the required doseand have been found to inhibit platelet aggregation, such as induced bythe addition of adenosine diphosphate, when added to platelet-richplasma.

The compounds according to the present invention can be administered fortheir anticoagulant effect over a wide dosage area. For instance, adosage of about 0.5 mg./kg. to 100 mg./kg. of body weight orallyadministered daily or on parenteral administration has proved to behighly effective.

The new compounds according to the present invention may find particularapplication in the treatment of thrombotic disease, especially of thearterial system, for instance, to inhibit thrombosis of the coronary orcerebral arteries.

The following new piperazine compounds according to the presentinvention have been found to be useful in therapy:

1-(4-chloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine

1-(3,4-dichloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine;

1-[(4-methoxy phenyl)-ethyl]-2-phenyl-4-(diethylaminoethyl)-piperazine;

1-[3-phenyl propyl-(1)]-2-phenyl-4-(diethylamino ethyl)-piperazine;

1-(4-chloro benzyl)-2-phenyl-4-(piperidino ethyl) piperazine;

1-(4-chloro benzyl)-2-phenyl-4-[1,3-dimorpholino propyl-(2)]piperazine;

1-(4-chloro benzyl)-3-phenyl-4-(diethylamino ethyl) piperazine.

The new piperazine compounds of the above given Formulas are obtainedaccording to the present invention, for instance, by reacting a1-R-substituted phenyl piperazine of Formula XIII. ##STR12## wherein##STR13## and R represent the above given groups and substituents, withan aralkyl halogenide of Formula XIV ##STR14## wherein X, Y, Z, and R₁represent the same substituents and numerals as given hereinabove, while

Hal is halogen.

Another method of producing the 1,4-substituted phenyl piperazinecompounds according to the present invention comprises reacting a1-aralkyl phenyl piperazine of Formula XV. ##STR15## wherein ##STR16##X, Y, Z, and R₁ represent the above given substituents, with a basicallysubstituted alkyl halogenide of Formula XVI ##STR17## wherein

Hal is halogen and R represents the above given substituent.

A further method of producing the 1,4-substituted phenyl piperazinecompounds according to the present invention comprises reacting a1-aralkyl phenyl piperazine, substituted in the ω-position by a reactivegroup Q, preferably by a halogen atom, and having the general FormulaXVII ##STR18## wherein ##STR19## X, Y, Z, and R₁ have the above givenmeaning, and R₆ is lower alkyl, with a corresponding secondary amine ofthe group consisting of a di-lower alkyl amine, such as dimethylamine,diethylamine, dipropylamine, or with piperidine, morpholine,pyrrolidine, piperazine, 3-ketopiperazine, or a lower N-alkylpiperazine.

If desired, the keto group in the resulting reaction product of FormulaV, wherein ##STR20## is either ##STR21## is reduced to the methylenegroup, so as to yield compounds of Formula V wherein ##STR22##represents either ##STR23##

The resulting basically substituted phenyl piperazine compounds ofFormula V may be converted, if desired, into their substantiallynon-toxic, pharmaceutically acceptable acid addition salts by methodswell known to the art. Not only physiologically tolerable salt-forminginorganic acids, such hydrochloric acid, sulfuric acid, phosphoric acid,hydrobromic acid, and others, but also organic acids, such as aceticacid, propionic acid, benzoic acid, salicyclic acid, succinic acid,malonic acid, citric acid, tartaric acid, fumaric acid, and others canbe used in the preparation of therapeutically valuable salts.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples serve to illustrate the present inventionwithout, however, limiting the same thereto.

EXAMPLE 1 1-(4'-Chloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine ##STR24## Method A: 1-(4'-Chloro benzyl)-2-phenyl piperazine

44 g. of 1-(4'-chloro benzyl)-2-phenyl-3-keto piperazine obtainedaccording to Example 1, Method A (a) of Application Ser. No. 333,497,are dissolved in 350 cc. of dioxane. The solution is added drop by dropto a suspension of 15 g. of lithium aluminum hydride LiAlH₄ in 800 cc.of ether while stirring thoroughly. After addition is completed, thereaction mixture is boiled under reflux for 12 hours. Thereafter, thelithium complex compound is decomposed and excess lithium aluminumhydride is destroyed by successively treating the reaction mixture with15 cc. of a 15% sodium hydroxide solution, with 15 cc. of water, with 45cc. of a 15% sodium hydroxide solution, and with 30 cc. of water. Theinorganic precipitate is removed by filtration and the filtered solutionis evaporated to dryness. The residue is recrystallized fromisopropanol. 37 g. of pure white crystals of the melting point 103°-104°C. are obtained.

Method B:

1-(4'-Chloro benzyl)-2-phenyl piperazine

142.4 g. of 1(4'-chloro benzyl)-2-phenyl-3-keto piperazine preparedaccording to Example 1, Method A (a) of Application Ser. No. 333,497,are suspended in 400 cc. of benzene while stirring vigorously. 800 cc.of a 1.5 molar solution of dibutyl aluminum hydride are then allowed torun slowly to said suspension. Thereby the reaction mixture is caused toboil under reflux. Half an hour after the addition is completed, themixture is cooled to 5° C. Excess dibutyl aluminum hydride is decomposedby careful addition of water. The precipitated aluminum hydroxide isdissolved in 40% sodium hydroxide solution. The separated organic layeris washed with 40% sodium hydroxide solution and then with water and isfreed of its organic solvent by evaporation. The residue isrecystallized from 1.5 l. of isopropanol.

Pure white crystals of the melting point 103°-104° C. are obtained in ayield corresponding to the theoretical yield. The resulting compound isidentical with the compound obtained according to Method A givenhereinabove as is proved by chromatography and infrared spectroscopy.

b. 1-(4'-Chloro benzyl)-2-phenyl-4-(diethylamino ethyl) piperazine

30 g. of the base prepared according to Methods A or B as describedhereinabove are dissolved in 100 cc. of toluene. The solution is boiledunder reflux with 20 g. of diethylamino ethylchloride and 20 g. offinely pulverized anhydrous potassium carbonate for 8 hours. By treatingthe reaction mixture with water, separating the toluene layer,extracting the base with hydrochloric acid, setting the base free fromits hydrochloride solution by addition of ammonia, and dissolving it inbenzene, the base is purified. After distilling off the solvent andrepeated distillation in a vacuum, 34 g. of a yellow oil of the boilingpoint 188°-199° C./0.09 mm. Hg are obtained. Yield: 81% of thetheoretical yield.

EXAMPLE 2 1-(3',4'-Dichloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine ##STR25##

a. 1-(3',4'-Dichloro benzyl)-2-phenyl-3-keto piperazine

140 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 163 g.of 3,4-dichloro benzylchloride in 1,600 cc. of acetone for 6 hours while330 cc. of triethylamine are added. The hot reaction mixture is filteredto remove precipitated triethyl ammonium chloride and is concentrated byfractional distillation. The resulting crystal fractions are twicerecrystallized from 4 l. of 96% ethanol.

162 g. of the above given reaction product of the melting point195°-208° C. (with decomposition) are obtained. Yield: 52% of thetheoretical yield.

b. 1-(3',4'-Dichloro benzyl)-2-phenyl piperazine

132 g. of the keto piperazine prepared as described hereinabove under(a) are dissolved in 200 cc. of dioxane. Said solution is added drop bydrop to a suspension of 21 g. of lithium aluminia hydride LiAlH₄ in 900cc. of absolute ether while the suspension is exposed to vibration.After the addition is completed, the mixture is boiled under reflux for12 hours. Successively 20 cc. of 15% sodium hydroxide solution, 20 cc.of water, 60 cc. of 15% sodium hydroxide solution, and 40 cc. of waterare added to the reaction mixture to cause decomposition of the complexcompound formed. The filtrate is freed of solvent, the residue isdistilled, and a viscous oil, boiling between 170° C./0.02 Torr. and178° C./0.02 Torr., is obtained. The oil crystallizes on triturationwith heptane. It is twice recrystallized from heptane. Yield: 110 g.corresponding to 87% of the theoretical yield.

c. 1-(3',4'-Dichloro benzyl)-2-phenyl-4-diethylamino ethyl) piperazine

40 g. of the piperazine compound prepared according to the methoddescribed hereinabove under (b), are boiled under reflux with 18.5 g. ofdiethylamino ethylchloride in 250 cc. of acetone with the addition of 52cc. of triethylamine for 12 hours. The triethyl ammonium-chloride formedthereby is filtered off. The resulting solution is concentrated byevaporation. Absolute ethanolic hydrochloric acid is added to theresidue. The precipitated hydrochloride is washed with ethanol and isdissolved in water. The base is set free from its aqueous solution bythe addition of ammonia and is extracted by means of benzene. Afterdrying over anhydrous potassium carbonate and removing the solvent, 34g. of a light yellow oil of the boiling point 192° C./0.03 mm. Hg areobtained. The yield is 65% of the theoretical yield.

EXAMPLE 3 1-[(4'-Methoxy phenyl) ethyl]-2-phenyl-4-(diethylamino ethyl)piperazine ##STR26##

a. 1-[(4'-Methoxy phenyl)ethyl]-2-phenyl-3-keto piperazine

140 g. of 2-phenyl-3-keto piperazine, 148.5 g. of 4-methoxy phenylethylchloride, and 330 cc. of triethylamine in 1.6 l. of acetone areboiled under reflux for 12 hours. The acetone is distilled off. 300 cc.of dimethylformamide are added to the residue and the mixture is heatedon the water bath for 36 hours. The major part of the dimethylformamideis distilled off in a vacuum. About 500 cc. of acetone and 150 cc. oftriethylamine are added to the residue. The mixture is freed oftriethylammoniumchloride by filtration while still boiling, and iscooled. After again distilling off the solvent, the remaining crystalsare washed with petroleum ether and are triturated with water. Theresulting solution is again filtered. On rendering the solutionalkaline, the reaction product is precipitated initially in oily form.It crystallizes very rapidly. After recrystallizing the crystals threetimes from isopropanol pure white crystals of the melting point142°-147° C. (with decomposition) are obtained. The yield is 110 g.corresponding to 44.7 % of the theoretical yield.

When carrying out the reaction from the beginning on in a mixture ofdimethylformamide and triethylamine, the yield is lower than whenproceeding as described hereinabove. This is due to formylation reactiontaking place thereby.

b. 1-[(4'-Methoxyphenyl)-ethyl]-2-phenyl piperazine

29 g. of the keto piperazine prepared as described hereinabove under(a), are dissolved in 200 cc. of absolute dioxane. A suspension of 8 g.of lithium aluminum hydride LiAlH₄ in 700 cc. of absolute ether is addeddrop by drop to said solution while stirring vigorously. Thereafter, themixture is boiled under reflux for 12 hours. After decomposing thereaction mixture by successive addition of 10 cc. of 15 % sodiumhydroxide solution, 10 cc. of water, 30 cc. of 15 % sodium hydroxidesolution, and finally of 20 cc. of water in the order given, the mixtureis freed from the precipitated inorganic salts by filtration and thefiltrate is concentrated by evaporation. Ethanolic hydrochloric acid isadded to the residue and the hydrochloride precipitated thereby isfiltered off by suction. The base is set free from the hydrochloride bythe addition of sodium hydroxide solution. 23 g. of a viscous oil areobtained. The oil crystallizes after standing for some time. It has aboiling point of 180°-185° C./0.01 mm. Hg. The yield is 83 % of thetheoretical yield.

c. 1-[(4'-Methoxy phenyl)-ethyl]-2-phenyl-4-(diethylamino ethyl)piperazine

18 g. of the base obtained as described hereinabove under (b) are boiledunder reflux with 30 g. of triethylamine and 12 g. of diethylaminoethylchloride in 120 cc. of acetone for 15 hours. The reaction solutionis cooled, filtered, and freed of the solvent by concentration byevaporation. The residue is dissolved in dilute hydrochloric acid. Thebase is set free from its hydrochloride solution by the addition ofammonia, is extracted with benzene, and the benzene extract is againfreed of its solvent. A mixture of acetone in ethanolic hydrochloricacid is added to the residue. The precipitated hydrochloride is filteredoff by suction. The base is again set free from its hydrochloride by theaddition of ammonia and is distilled in a vacuum. 17 g. of a viscous oilof the boiling point 215° C./0.002 mm. Hg are obtained. The yield is 70% of the theoretical yield.

EXAMPLE 4 1-[3'-Phenyl propyl-(1)]-2-phenyl-4-(diethylamino ethyl)piperazine ##STR27##

a. 1-[3'-Phenyl propyl-(1)]-2-phenyl-3-keto piperazine

140 g. of 2-phenyl-3-keto-piperazine and 135 g. of 3-phenylpropylchloride(1) are heated on the water bath in 350 cc. ofdimethylformamide with the addition of 330 cc. of triethylamine for 48hours. The major portion of the dimethylformamide and the triethylamineare distilled off in a vacuum. The residue is dissolved in 2 l. ofacetone. 150 cc. of triethylamine are added to said acetone solution.The mixture is boiled under reflux for 10 minutes. The solution is thencooled to 30° C. and is freed from triethyl ammoniumchloride byfiltration. The keto-piperazine crystallizes from the resulting filtrateon cooling in a mixture of ice and sodium chloride. The crystals arepurified by recrystallization from isopropanol and 50 % ethanol. 110 g.of white crystals of the melting point 114°-116° C. are obtained. Theyield is 47 % of the theoretical yield.

b. 1-[3'-Phenyl propyl-(1)]-2-phenyl piperazine

43 g. of the keto-piperazine obtained as described hereinabove under (a)are dissolved in 200 cc. of dioxane and are reduced by the addition of10 g. of lithium aluminum hydride LiAlH₄ suspended in 800 cc. of etheras described in the preceding examples. After decomposing the reactionmixture and recovering the base by purification via its hydrochloride,30 g. of a viscous oil of the boiling point 155°-160° C./0.01 mm. Hg areobtained. The yield is 73 % of the theoretical yield.

c. 1-[3'-Phenyl propyl-(1)]-2-phenyl-4-(diethylamino ethyl) piperazine

23 g. of the base prepared as described hereinabove under (b) are boiledunder reflux with 13.5 g. of diethylamino ethylchloride, 35 cc. oftriethylamine, and 150 cc. of acetone for 10 hours. After recovering thebase as described in the preceding examples and purifying it via itshydrochloride, 22 g. of a colorless oil of the boiling point 187°-189°C./0.01 mm. Hg are obtained. The yield is 70.5 % of the theoreticalyield.

EXAMPLE 5 1-(4'-Chloro benzyl)-2-phenyl-4-(piperidino ethyl) piperazine##STR28##

31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according toExample B), 25 g. of piperidino ethylchloride, 20 g. of triethylamine,and 250 cc. of acetone are boiled under reflux for 18 hours. Thefiltered reaction solution is freed of its solvent by concentration byevaporation. The residue is dissolved in benzene. The benzene solutionis washed with water. After drying and distilling off the solvent, thebase is obtained in the form of a viscous, yellow oil on distillation at210° C./0.06 Torr. The oil crystallizes on trituration with isopropanol.After twice recystallizing the crystals from n-heptane (41 g. of yellowcrystals of the melting point 85°-87° C.) are obtained. The yield is 95% of the theoretical yield.

In place of acetone there may also be used other solvents, for instance,benzene, toluene, or xylene and, in place of triethylamine, forinstance, pyridine, dimethylaniline, potassium carbonate, sodium amideor sodium hydride.

In a similar manner as described in Example 6 are obtained:

1-(4'-Chloro benzyl)-2-phenyl-4-pyrrolidino ethyl) piperazine, boilingpoint 200°-205° C./0.05 mm. Hg; melting point of the hydrochloride254°-258° C. (decomposition), by reaction of 1-(4'-chlorobenzyl)-2-phenyl piperazine and pyrrolidino ethyl chloride.

1-(4'-Chloro benzyl)-2-phenyl-4-[4'-methyl piperazinoethyl-(1)]piperazine, boiling point 215°-217° C./0.005 mm. Hg; meltingpoint of the hydrochloride 252°-270° C. (decomposition), by reaction of1-(4'-chloro benzyl)-2-phenyl piperazine and 1-(3-chloro ethyl)-4-methylpiperazine.

EXAMPLE 6 1-(4'-Chloro benzyl)-2-phenyl-4-[1",3"-dimorpholinopropyl(2")]-piperazine ##STR29##

31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according toExample B, 52 g. of 1,3-dimorpholino propylchloride-(2), prepared bychlorinating 1,3-dimorpholino propanol-(2), 25 g. of triethylamine, and250 cc. of acetone are boiled under reflux for 48 hours. The baseremaining after filtration and evaporation of the solvent is purified bydissolving it in hydrochloric acid and setting it free from itshydrochloride solution by the addition of ammonia. The base is dissolvedin benzene, and the benzene solution dried over anhydrous potassiumcarbonate. After distilling off the solvent, the residue is distilled ina vacuum of 0.1 Torr. The first fraction distilling over at atemperature up to 110° C. consists mainly of unreacted dimorpholinopropylchloride. The remaining residue is dissolved in petroleum etherand is separated from undissolved matter by filtration after cooling.The solvent is distilled off and the remaining compound is purified bydistillation in a vacuum. 34 g. of an oil of the boiling point 230°C./0.001 mm. Hg are obtained. The oil solidifies on standing.

EXAMPLE 7 1-(4'-Chloro benzyl)-3-phenyl-4-(diethylamino ethyl)piperazine ##STR30##

a. 1-(Diethylamino ethyl)-2-phenyl piperazine

1-(Diethylamino ethyl)-2-phenyl-3-keto piperazine is prepared byreacting N₁ -(diethylamino ethyl) ethylenediamine with α-chloro phenylacetylchloride and isolating the above mentioned reaction product fromthe resulting mixture of isomers.

89 g. of said keto piperazine dissolved in 200 cc. of dioxane are addeddrop by drop to a suspension of 20 g. of lithium aluminum hydride LiAlH₄in 800 cc. of ether. After addition of the keto piperazine, the reactionmixture is boiled under reflux for 6 hours. It is then decomposed bysuccessively adding 20 cc. of 15% sodium hydroxide, 20 cc. of water, 60cc. of 15% sodium hydroxide solution, and finally 40 cc. of water. Thefiltered solution is concentrated by evaporation and the residue isdistilled in a vacuum. The resulting oil which distills at a temperaturebetween 102° C. and 115° C./0.05 mm. Hg, is dissolved in benzene and isextracted therefrom by shaking in 10 % hydrochloric acid. The base isset free from its hydrochloride solution by the addition of 10 % sodiumhydroxide solution and is repeatedly distilled in a vacuum. An almostcolorless oil of the boiling point 114°-117° C./0.07 mm. Hg is obtained.The yield corresponds to the theoretical yield. The compound contains asmall amount of 3-phenyl-1-(diethylamino ethyl) piperazine.

b. 1-(4'-Chloro benzyl)-3-phenyl-4-diethylamino ethyl) piperazine

26 g. of the base prepared as described hereinabove under (a) are boiledunder reflux with 17.7 g. of 4-chloro benzylchloride and 42 cc. oftriethylamine in 200 cc. of acetone for 10 hours. After filtration anddistilling off the solvent, the base is purified in the manner describedhereinabove via its hydrochloride and is set free from saidhydrochloride by the addition of ammonia. The residue is freed of thesolvent and is dissolved in acetic acid ethyl ester. The hydrochlorideis precipitated from said solution by the addition of absolute ethanolichydrochloric acid. The hydrochloride is recrystallized from acetic acidethyl ester. The base is set free from said hydrochloride by means ofammonia and is distilled in a vacuum. An almost colorless oil of theboiling point 180° C./0.01 mm. Hg is obtained. The yield is 30 g.corresponding to 78 % of the theoretical yield.

This compound can be distinguished by means of its infrared spectrumfrom the isomeric 1-(4'-chloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine by directly comparing both compounds.

EXAMPLE 8 1-(Diethylamino ethyl)-2-phenyl-4-(p-ethoxy benzyl) piperazine##STR31##

(a) 1-Diethylamino ethyl-2-phenyl-3-keto piperazine

144 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 121 g.of diethylamino ethylchloride, 340 cc. of triethylamine, and 1600 cc. ofacetone for 24 hours. The cooled solution is filtered to removetriethylamine hydrochloride and the filtrate is evaporated to dryness.The residue is dissolved in water, 40 % sodium hydroxide solution isadded thereto, and the oil which forms as upper layer, is extracted withbenzene. The benzene solution is dried over anhydrous potassiumcarbonate, the benzene is removed by distillation, and the residue isdistilled in a vacuum. A light yellow, viscous oil of the boiling point175° C./0.05 mm. Hg is obtained. The oil is twice recrystallized fromn-heptane. 145 g. of the above mentioned compound melting at 53°-56° C.are obtained. The yield is 64 % of the theoretical yield.

b. 1-Diethylamino ethyl-2-phenyl piperazine

89 g. of the keto piperazine prepared as described hereinabove under(a), are dissolved in 200 cc. of absolute dioxane. The solution is addedto a suspension of 20 g. of lithium aluminum hydride LiAlH₄ in 800 cc.of absolute ether while exposing the mixture to vibration. Afteraddition of the keto piperazine solution is completed, the reactionmixture is boiled under reflux for 6 hours. Thereafter it is decomposedby successive treatment with 21 cc. of 15 % sodium hydroxide solution,21 cc. of water, 63 cc. of 15 % sodium hydroxide solution, and 42 cc. ofwater. The decomposed reaction mixture is filtered, the solvent isremoved by distillation, and the residue is distilled in a vacuum. 65 g.of a light yellow oil of the boiling point 114°-117° C./0.05 mm. Hg areobtained. This oil corresponds to the above given compound. The yield is77 % of the theoretical yield.

c. 1-Diethylamino ethyl-2-phenyl-4-(p-ethoxy benzyl) piperazine

40 g. of the piperazine derivative prepared as described hereinaboveunder (b) are boiled under reflux with 27 g. of p-ethoxy benzylchloridein 400 cc. of acetone with the addition of 50 cc. of triethylamine for12 hours. The triethyl ammonium hydrochloride formed thereby is filteredoff. The acetone is removed by distillation. The residue is dissolved inbenzene and the base is dissolved therefrom in the form of itshydrochloride by extraction with dilute hydrochloric acid. The base isset free from its hydrochloride solution by the addition of ammonia andis extracted with benzene. The benzene solution is dried over anhydrouspotassium carbonate. The solvent is distilled off and the residue isdistilled in a vacuum. 39 g. of a light yellow viscous oil of theboiling point 200° C/0.05 mm. Hg are obtained. The yield is 64 % of thetheoretical yield.

EXAMPLE 9 1-Diethylamino ethyl-3-phenyl piperazine

1-Diethylamino ethyl-2-keto-3-phenyl piperazine prepared according toExample 1 B (a) of application Ser. No. 333,497, is reduced by followingthe procedure described hereinabove in Example 7 (a) whereby, in placeof 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecularamount of said 1-diethylamino ethyl-2-keto-3-phenyl piperazine isreduced. The resulting 3-phenyl piperazine compound is obtained in theform of a light yellow oil boiling at 102° C./0.02 mm. Hg.

EXAMPLE 10 1-Benzyloxy benzyl-2-phenyl piperazine

1-Benzyloxy benzyl-2-phenyl-3-keto piperazine prepared according toExample 12, is reduced by following the procedure described hereinabovein Example 8 (a) whereby, in place of 1-diethylaminoethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said1-benzyloxy benzyl-2-phenyl-3-keto piperazine is used. The resulting2-phenyl piperazine compound is obtained in the form of white crystalsmelting at 140-141° C.

EXAMPLE 11 1-(3',4',5'-Trimethoxy benzyl)-2-phenyl piperazine

1-(3',4',5'-Trimethoxy benzyl)-2-phenyl-3-keto piperazine preparedaccording to Example 13, is reduced by following the procedure describedhereinabove in Example 8 (a) whereby, in place of 1-diethylaminoethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said1-(3',4',5'-trimethoxy benzyl-2-phenyl-3-keto piperazine is used. Theresulting 2-phenyl piperazine compound is obtained in the form of ayellow oil boiling at 185-195° C./0.08 mm. Hg.

EXAMPLE 12 1-[3'-(4"-Methoxy phenyl) propyl(1) ]-2-phenyl piperazine

1-[3'-(4"-Methoxy phenyl) propyl(1)]-2-phenyl-3-keto piperazine preparedaccording to Example 14, is reduced by following the procedure describedhereinabove in Example 8 (a) whereby, in place of 1-diethylaminoethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said1-[3'-(4"-methoxy phenyl) propyl(1)]-2-phenyl-3-keto piperazine is used.The resulting 2-phenyl piperazine is obtained in the form of a lightyellow oil boiling at 176° C./0.05 mm. Hg.

EXAMPLE 13 1-(4'-Chloro benzyl)-3-phenyl-4-diethylamino ethyl piperazine

1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazineprepared according to Example 10, is reduced by following the proceduredescribed hereinabove in Example 8 (a) whereby, in place of1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecularamount of said 1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethylpiperazine is used. The resulting 3-phenyl piperazine compound isobtained in the form of a light yellow oil boiling at 180° C./0.01 mm.Hg.

EXAMPLE 14 1-(3',4'-Dichloro benzyl)-2-phenyl-4-dimethylamino ethylpiperazine

1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according toExample 3 (b), is alkylated by following the procedure described inExample 3 (c), whereby, in place of the diethylamino ethylchloride, theequimolecular amount of dimethylamino ethylchloride is used. Theresulting reaction product is obtained in the form of a light yellow oilboiling at 190° C./0.01 mm. Hg.

EXAMPLE 15 1-(3',4'-Dichloro benzyl)-2-phenyl-4-morpholino ethylpiperazine

1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according toExample 3 (b), is akylated by following the procedure described inExample 3 (c) whereby, in place of diethylamino ethylchloride, theequimolecular amount of morpholino ethylchloride is used. The resultingreaction product is obtained in the form of a light yellow oil boilingat 230° C./0.04 mm. Hg.

EXAMPLE 16 1-(3',4'-Dichloro benzyl)-2-phenyl-4-diethylamino propylpiperazine

1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according toExample 2 (b), is alkylated by following the procedure described inExample 2 (c) whereby, in place of the diethylamino ethylchloride, theequimolecular amount of diethylamino propylchloride is used. Theresulting reaction product is obtained in the form of a light yellow oilboiling at 210° C./0.04 mm. Hg.

EXAMPLE 17 1-(4'-Benzyloxy benzyl)-2-phenyl-4-diethylamino ethylpiperazine

1-(4'-Benzyloxy benzyl)-2-phenyl piperazine prepared according toExample 10, is alkylated by means of diethylamino ethylchloride byfollowing the procedure described in Example 2 (c). The resultingreaction product is obtained in the form of a light yellow oil boilingat 235° C./0.01 mm. Hg.

EXAMPLE 18 1-(3',4',5'-Trimethoxy benzyl)-2-phenyl-4-diethylamino ethylpiperazine

1-(3',4',5'-Trimethoxy benzyl)-2-phenyl piperazine prepared according toExample 11, is alkylated by means of diethylamino ethylchloride byfollowing the procedure described in Example 2 (c). The resultingreaction product is obtained in the form of yellow oil boiling at 200°C./0.03 mm. Hg.

EXAMPLE 19 1-[3'-(4"-Methoxy phenyl) propyl(1)]-2-phenyl-4-diethylaminoethyl piperazine

1-[3'-(4"-Methoxy phenyl) propyl(1)]-2-phenyl piperazine preparedaccording to Example 12, is alkylated by means of diethylaminoethylchloride by following the procedure described in Example 2 (c). Theresulting reaction product is obtained in the form of a yellow oilboiling at 130°-190° C./0.01 mm. Hg.

EXAMPLE 20 1-(4'-Ethoxy benzyl)-3-phenyl-4-diethylamino ethyl piperazine

1-Diethylamino ethyl-2-phenyl piperazine prepared according to Example 7(a), is reacted with 4-ethoxy benzylchloride by following the proceduredescribed in Example 7 (b) and using, in place of 4-chlorobenzylchloride, the equimolecular amount of 4-ethoxy benzylchloride. Theresulting reaction product is obtained in the form of a yellow oilboiling at 200° C./0.05 mm. Hg.

EXAMPLE 21 1-(4'-Chloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine ##STR32##

A. 1-(4-Chloro benzyl)-2-phenyl-4-(β-hydroxy ethyl) piperazine ##STR33##

a. 30 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine, prepared accordingto Example 1 A), 20 g. of ethylene chlorohydrin, 20 g. of triethylamineand 250 cc. of methyl ethyl ketone are boiled under reflux for 24 hours.After cooling, the triethylamine hydrochloride formed thereby is removedby filtration, the filtrate is evaporated in a vacuum, the residue isdissolved in benzene, the benzene solution is washed with water anddried over anhydrous potassium carbonate. The benzene is removed bydistillation and the residue is distilled in a vacuum. A yellow, viscousoil of the boiling point 195° C./0.01 mm. Hg is obtained. The oil istwice recrystallized from isopropanol and then from n-heptane. Meltingpoint 91-94° C.; yield 22 g.

b. A mixture of 28.6 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine, 6.0g. of ethylene oxide and 200 cc. of methanol is let standing for 4 daysin a closed flank at room temperature. Then the methanol is distilledoff and the residue is distilled at 193° C./0.01 mm. Hg. The base istwice recrystallized from n-heptane, whereby a product having a meltingpoint of 91°-94° C. is obtained. Yield 19 g.

c. 50 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine are dissolved in100 cc. of dioxane. To this solution are added 31 g. of acetylglycolicacid chloride, dissolved in 50 cc. of dioxane. The mixture boiled for 2hours under reflux. The dioxane is distilled off in a vacuum and theresidue is dissolved in benzene; the benzene solution is washed with anaquous 10 % sodium hydroxide solution and is dried over anhydrouspotassium carbonate. The solvent is distilled off and the residue isrecrystallized three times from isopropanol. Melting point 136°-137° C.;yield 46 g.

44 g. of the piperazine derivative obtained as above are dissolved in120 cc. of absolute dioxane and added slowly drop to drop to asuspension of 10 g. of LiAlH₄ in 700 cc. of absolute ether. The mixtureis boiled under reflux for 2.5 hours. It is then decomposed by adding 10cc. of 15 % sodium hydroxide solution, 10 cc. of water, 30 cc. of 15 %sodium hydroxide solution and 20 cc. of water. The precipitatedinorganic material is separated by filtration and the solvent isdistilled in a vacuum. The residue is recrystallized three timed fromn-heptane. The obtained compound has a melting point of 91°-94° C. Yield17 g.

B. 1-(4'-Chloro benzyl)-2-phenyl-4-(2-chloro ethyl)pierazinehydrochloride. ##STR34##

24 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-hydroxy ethyl) piperazineare dissolved in 150 cc. of chloroform and added drop by drop to asolution of 15 g. of thionyl chloride in 150 cc. of chloroform. Themixture is boiled under reflux for 5 hours and the solvent is removed ina vacuum by heating the mixture in a water bath. Excess of absoluteethanolic hydrochloric acid is added and the remaining acid is distilledoff. The crystalline residue obtained is recrystallized from absoluteethanol. Melting point 178°-195° C. (dec.); yield 30 g.

C. 1-(4'-Chloro benzyl)-2-phenyl-4-(diethylaminoethyl) piperazine.

20 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazinehydrochloride, 14 g. of diethylamine and 200 cc. of acetone are boiledunder reflux for 12 hours. After cooling, the precipitated diethylaminohydrochloride is filtered off with suction and the solvent of thefiltrate is evaporated in a vacuum. The residue is distilled in avacuum. 15 g. of a light yellow oil having a boiling point of 190°C./0.06 mm. Hg are obtained. This product is identical with the productas obtained according to Example 1 B.

EXAMPLE 22 1-(4'-Chloro benzyl)-2-phenyl-4-[(4"-methyl)-piperazinoethyl-(1)] piperazine. ##STR35##

47 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazinehydrochloride, 16.5 g. of N-methyl piperazine, 75 cc. of triethylamineand 300 cc. of methyl ethyl ketone are boiled under reflux for 12 hours.After cooling the precipitated triethylamino hydrochloride is filteredoff with suction and the solvent is distilled off in a vacuum. Theresidue is dissolved in benzene, the benzene solution is washed withwater and dried over anhydrous potassium carbonate. The solvent isdistilled off and the residue is disssolved in absolute ethanol.Absolute ethanolic hydrochloric acid is added to precipitate thehydrochloride salt. After cooling the precipitation is separated byfiltration, washed with absolute ethanol and dried. Melting point250°-269° C. (decomposition). To obtain the free base the hydrochlorideis dissolved in water and the base is set free from its hydrochloridesolution by the addition of ammonia and extracted with benzene. Thebenzene solution is dried over anhydrous potassium carbonate, thesolvent is distilled off and the residue is distilled in a vacuum.Boiling point 220-223° C./0.01 mm. Hg. Yield 30 g.

EXAMPLE 23 1-(4'-Chloro benzyl)-2-phenyl-4-[(3"-keto)piperazinoethyl-(1")] piperazino.

25 g. of 1-(4"-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazinehydrochloride, 7.3 g. of mono keto piperazine, 200 cc. of methyl ethylketone and 200 cc. of triethylamine are boiled for 24 hours underreflux. The precipitated triethylamine hydrochloride is filtered offwith suction. Then, the solvent is evaporated, the residue is dissolvedin benzene and the benzene solution is washed with water and dried overanhydrous potassium carbonate. The solvent is distilled off and theresidue is distilled at 230°-250° C./0.06 mm. Hg (minor decomposition).The distilled product is dissolved in ether, washed with 0.5Nhydrochloric acid. The extract obtained with the diluted hydrochloricacid is treated with carbon aand after filtration, the base is set freefrom said solution by use of ammonia. The base is dissolved in benzene,dried over anhydrous potassium carbonate and after evaporation of thesolvent, the residue is distilled at 220°-230° C. (air bathtemperature)/0.005 mm. Hg. A very viscous, brownish oil is obtained.

The acid addition salts of the bases according to the present inventionare prepared in a manner known per se. For instance, anhydrous ethanolichydrochloric acid is added to the base whereby the hydrochlorideprecipitates and is isolated by filtration. Or the base is trituratedwith the equimolecular amount of the respective acid either as such orin aqueous solution or in solution in an organic solvent and, ifrequired, evaporating the solvent.

Specific procedures to prepare the acid addition salts are thefollowing:

To prepare the hydrochlorides, the bases are dissolved in absoluteethanol and an equimolecular amount of abslute ethanolic hydrochloricacid is added. After cooling, the precipitated hydrochloride isseparated by filtration and recrystallised from absolute ethanol orisopropanol.

The succinates or fumarates, respectively, may be obtained using anequimolar amount succinic acid or fumaric acid, respectively, which isadded and to the base dissolved in acetone. After boiling under reflux,e.g. for 2 hours, the mixture is cooled and the precipitated salts areseparated. The so obtained salts are pure for analysis. In case that thefumarates or succinates, respectively, are not separated from themixture in crystalline form, the solvent is evaporated and the remainingsyrup is triturated to induced crystallization. Recrystallization may beeffected by use of ethyl acetate.

To prepare the sulfates, the base is dissolved in absolute ethanol andan equimolecular amount of dilute sulfuric acid is added. The obtainedsulfates may be recrystallized from ethanol.

The preparation of the phosphates may be effected by dissolution of thebase in absolute ethanol, and addition of an equimolecuar amount ofdilute phosphoric acid. The phosphate may be precipitated by use ofacetic acid ethyl ester and may be recrystallized by use of isopropanol.

The following acid addition salts have been prepared and isolated:

    __________________________________________________________________________    Ex-                      Acid addi-                                           ample                                                                              Base                tion salt Melting point                              __________________________________________________________________________    24   1-(4'-Chloro benzyl)-2-phenyl-                                                                    Dihydro-  255-1270° C. with                        4-diethylamino ethyl piperazine                                                                   chloride  decomposition                              25   1-(3',4'-Dichloro benzyl)-2-                                                                      Dihydro-  220-222° C.                              phenyl-4-diethylamino ethyl                                                                       chloride                                                  piperazine                                                               26   1-(3',4'-Dichloro benzyl)-2-                                                                      o-Phos-   220-226° C.                              phenyl-4-diethylamino ethyl                                                                       phate                                                     piperazine                                                               27   1-(3',4'-Dichloro benzyl)-2-                                                                      Sulfate   210-214° C.                              phenyl-4-diethylamino ethyl                                                   piperazine                                                               28   1-(4'-Chloro benzyl)-2-phenyl-                                                                    Succinate 156-158° C.                              4-piperidino ethyl piperazine                                            29   1-(4'-Chloro benzyl)-2-phenyl-4-                                                                  Fumar-    190° C. sublimates                       piperidino ethyl piperazine                                                                       ate       250-251° C. with de-                                                   composition                                30   1-[(4'-Methoxy phenyl)ethyl]-                                                                     Hydro-    190-201° C.                              2-phenyl-4-diethylamino ethyl                                                                     chloride                                                  piperazine                                                               31   1-[3"-Phenyl propyl(1)]-2-                                                                        Hydrochloride                                                                           185-192° C.                              piperazine                                                               32   1-(4'-Chloro benzyl)-3-phenyl-                                                                    Hydrochloride                                                                           241-255° C.                              4-diethylamino ethyl piperazine                                                                             with decom-                                                                   position                                   33   1-(4'-Chloro benzyl)-2-phenyl-                                                                    Succin-    95-101° C.                              4-diethylamino ethyl piperazine                                                                   ate                                                  __________________________________________________________________________

EXAMPLE 34 4-Diethylaminoethyl-3-phenyl-1-o-hydroxy benzyl) piperazine##STR36##

a. 4-Diethylaminoethyl-3-phenyl-1-(o-acetoxy benzoyl)piperazine isprepared by boiling under reflux 15 g. of1-diethylaminoethyl-2-phenyl-piperazine dissolved in 100 ml. of methylethyl ketone with 11 g. of acetyl salicyclic acid chloride dissolved in50 ml. methyl ethyl ketone, for 6 hours. The solvent is removed bydistillation. The residue is dissolved in water. The aqueous solution isextracted with benzene. Ammonia is added to the aqueous layer until itsreaction is alkaline and the thus precipitated oil is extracted withbenzene. The benzene extract is dried by means of potassium carbonateand the benzene is distilled off. The residue is distilled in a vacuum.Boiling point: 190° C./0.01 mm. (bath temperature). Light yellow,viscous oil.

b. 4-Diethylaminoethyl-3-phenyl-1-(o-hydroxy benzoyl) piperazine isobtained by dissolving the reaction product prepared as describedhereinabove under (a) in 100 ml. of dilute hydrochloric acid (2 : 100).The solution is heated to 50° C. for one hour an is then renderedalkaline by the addition of ammonia. The precipitated viscous product isextracted with benzene, the benzene solution is dried by means ofpotassium carbonate. The benzene is removed by distillation and theresidue is distilled in a vacuum. Boiling point: 180° C./0.001 mm. (bathtemperature). Light yellow, vitreous product.

c. 4-Diethylaminoethyl-3-phenyl-1-(o-hydroxy benzyl) piperazine isobtained by dissolving 40 g. of4-diethylaminoethyl-3-phenyl-1-(o-hydroxy benzoyl) piperazine in 150 ml.of dioxane and slowly adding said solution to a suspension of 6 g. oflithium aluminum hydride in 800 ml. of absolute ether. The reactionmixture is boiled under reflux for two hours. The resulting complexcompound is decomposed by a treatment with 5 ml. of 15% sodium hydroxidesolution followed by 5 ml. of water, 15 ml. of 15% sodium hydroxidesolution, and finally 10 ml. of water. The resulting precipitate isfiltered off and the solvent is distilled off from the filtrate. Theresidue is distilled in a vacuum. Boiling point: 180° C./0.001 mm. (bathtemperature). Yellow oil.

EXAMPLE 35 1-(p-Hydroxy benzyl)-2-phenyl-4-diethylaminoethyl piperazine##STR37##

a. 1-(4-Benzyloxy benzyl)-2-phenyl-3-keto piperazine is obtained byboiling under reflux 48 g. of 4-benzyloxybenzyl chloride, 35 g. of2-phenyl-3-keto piperazine, 500 ml. of acetone, and 50 ml. oftriethylamine for 14 hours. Thereafter, the acetone is distilled off andthe residue is treated with water. The precipitated crystals arefiltered of and are recrystallized from dioxane and thereafter from amixture of dimethylformamide and water (1 : 1). Melting point: 207°-211°C. White crystals.

b. 1-(4-Benzyloxybenzyl)-2-phenyl piperazine is obtained by suspending39 g. of the compound prepared according to (a) hereinabove in 150 ml.of dioxane. The suspension is added to a suspension of 10 g. of lithiumaluminum hydride (LiAlH₄) in 900 ml. of ether. The resulting mixture isboiled under reflux for two hours. The complex compound formed therebyis decomposed by treatment with 10 ml. of 15% sodium hydroxide solution,followed by a treatment with 10 ml. of water, 30 ml. of 15% sodiumhydroxide solution, and finally with 20 ml. of water. The decomposedmixture is filtered. The filter residue is discarded. The filtrate isevaporated to dryness and the evaporation residue is recrystallized fromdioxane. melding point: 140°-141° C., white crystals.

c. 1-(4-Benzyloxybenzyl)-2-phenyl-4-diethylaminoethyl piperazine isobtained by boiling under reflux 25 g. of the compound preparedaccording to (b) hereinabove with 10.5 g. of diethylaminoethyl chloride,30 ml. of triethylamine. and 200 ml. of acetone for six hours. Theprecipitated triethylamine hydrochloride is filtered off. The acetone isdistilled of and the residue is dissoved in benzene. The benzenesolution is extracted with dilute hydrochloric acid (1 : 10). The acidsolution is made alkaline by the addition of ammonia and theprecipitated oil is extracted with benzene. After distilling off thebenzene, the residue is distilled in a vacuum. Boiling point: 235°C./0.01 mm. Yellow oil.

d. 1-(p-Hydroxybenzyl)-2-phenyl-4-diethylamino ethyl piperazine isobtained by dissolving 15 g. of the compound prepared as described under(c) in 500 ml. of toluene. 5 g. of palladium deposited on asbestos areadded thereto. Hydrogen is passed into the solution under a positivepressure of 15 mm. mercury. Progress of the hydrogenating debenzylationis ascertained by thin-layer chromatography. Introduction of hydrogen isdiscontinued after 20 hours. The catalyst is filtered off. The tolueneis distilled off and the residue is triturated with petroleum ether. Theprecipitated crystals are filtered off by suction. The filter residue isdissolved in warm acetone and is precipitated by the addition ofpetroleum ether. After filtering off by suction the precipitate anddrying it, white crystals of the melting point 108°-112° C. areobtained.

EXAMPLE 36 1-(3,4-Dihydroxy benzyl)-2-phenyl-4-diethylaminoethylpiperazine ##STR38## The compound is prepared in an analogous manner asdescribed in Example 35 by using as starting material1-(3,4-dibenzyloxybenzyl)-2-phenyl-3-keto piperazine. Light yellow, veryviscous oil. Boiling point: 245° C./0.001 mm. EXAMPLE 374-Diethylaminoethyl-3-phenyl-1-(3,4-dibenzyloxy benzyl) piperazinehydrochloride. ##STR39## 30 g. of 3,4-dibenzyloxy benzylchloride, 23 g.of 1-diethylamino ethyl-2-phenyl piperazine, 20 ml. of triethylamine,and 200 ml. of methylethylketone are boiled under reflux for 12 hours.The precipitated triethylamine hydrochloride is filtered off by suction.The solvent is distilled off and the residue is dissolved in benzene.The benzene solution is extracted with dilute hydrochloric acid (1 : 8).The hydrochloric acid extract is rendered alkaline by the addition ofammonia and is extracted with benzene. The benzene is removed from thebenzene extract by distillation. Water-free alcoholic hydrochloric acidis added to the residue, and the hydrochloride of the resulting base isprecipitated by the addition of a mixture of petroleum ether and acetone(1 : 1). The hydrochloride is redissolved in alcohol and is againprecipitated by the addition of petroleum ether and acetone. Meltingpoint of the hydrochloride: It starts to sublimate at 203° C. and meltsat 235°-239° C. with decomposition. White crystals. EXAMPLE 381-(p-Chloro benzyl)-2-phenyl-4-morpholino ethyl-3-keto piperazine##STR40##

45 g. of 1-(4-chloro benzyl)-2-phenyl-3-keto piperazine,

56 g. of morpholino ethylchloride,

50 g. of potassium carbonate, and

500 ml. of toluene

are boiled under reflux for 20 hours. Water is added to the reactionmixture and undissolved matter is filtered off therefrom. The cleartoluene solution is extracted with 250 ml. of N hydrochloric acid. Theextract is rendered strongly alkaline by the addition of ammonia and theprecipitated base is extracted with benzene. After drying the benzeneextract, the solvent is distilled off and the residue is recrystallizedfrom isopropanol, yielding a first crystal fraction. The mother lye isconcentrated by evaporation to a small volume and is cooled.Precipitated crystals are filtered off by suction. They represent thesecond crystal fraction. Since both fractions still contain unreactedstarting material, they are triturated with 60 ml. of N acetic andundissolved matter is filtered off. The clear acetic acid solution isrendered strongly alkaline by the addition of ammonia and is extractedwith benzene. The benzene is distilled off after drying the extract. Theremaining residue is recrystallized from isopropanol. Melting point:117°-119° C. Yield: 10 g.

EXAMPLE 39 1-(2-Chloro benzyl)-2-phenyl-4-morpholino ethyl-3-ketopiperazine ##STR41## 45 g. of 1-(2-chloro benzyl)-2-phenyl-3-ketopiperazine obtained as described in Example 46 (a),

56 g. of morpholino ethyl chloride,

50 g. of potassium carbonate, and

500 ml. of toluene

are boiled under reflux for 20 hours. The reaction mixture is pouredinto water. Undissolved matter is separated. The toluene solution isextracted with 250 ml. of N hydrochloric acid. The hydrochloric acidextract is rendered strongly alkaline by the addition of ammonia and theprecipitated base is extracted with benzene. After drying, the solventis distilled off from the extract. The residue is dissolved in 100 ml.of N acetic acid. The crystals formed after allowing the solution tostand for a short period of time, are separated. The acetic acidfiltrate is rendered strongly alkaline by the addition of ammonia andthe precipitated base is extracted with benzene. After drying thebenzene extract and distilling off the solvent, the residue isrecrystallized from ispropanol. Melting point: 104°-106° C. Yield: 8.5g.

EXAMPLE 40 1-(p-Chloro benzyl)-2-phenyl-4-dimethylamino propylpiperazine ##STR42## 28.6 g. of 1-(p-chloro benzyl)-2-phenyl piperazine,15.0 g. of dimethylaminopropylchloride,

50 ml. of triethylamine, and

100 ml. of methyl ethyl ketone

are boiled under reflux for 20 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The solvent isdistilled off. The residue is dissolved in 100 cc. of N hydrochloricacid. The hydrochloric acid extract is twice washed with benzene and isthen rendered alkaline by the addition of ammonia. The oily base isseparated in a separating funnel and is dissolved in 100 ml. ofisopropanol. Solid potassium hydroxide is added to the isopropanolsolution in order to remove the water present therein. The isopropanolsolution is then filtered through a layer of potassium carbonate. Afterdistilling off the solvent, a yellow viscous oil is obtained. The oil isdissolved in 1.5 liters of petroleum ether. Small amounts of impuritiesare filtered off and the petroleum ether is distilled off. The crudebase is dissolved in benzene and is extracted with 25% acetic acid. Thebase is set free from said extract by the addition of ammonia. The baseis again dissolved in benzene and dried by means of potassium carbonate.The solvent is distilled off and the residue is distilled in a vacuum.Boiling point: 180°-184° C./0.08 mm. Yield: 14 g.

EXAMPLE 41 1-(3,4-Dibenzyloxy benzyl)-2-phenyl-4-diethylamino ethylpiperazine fumarate ##STR43##

a. 23.2 g. of 2-phenyl-3-keto piperazine,

50.0 g. of 3,4-dibenzyloxy benzylchloride,

30 ml. of triethylamine, and

300 ml. of methyl ethyl ketone

are boiled under reflux for 3 hours. After cooling, precipitatedtriethylamine hydrochloride is filtered off by suction. The solvent isthen distilled off. The residue is dissolved in 50 ml. of acetone. Theacetone solution is poured into 500 ml. of water. The precipitatedcrystallized product is filtered off and is twice recrystallized fromisopropanol. Melting point: 108°-110° C. Yield 46 g.

b. 44 g. of the compound as described hereinabove under (a) aresuspended into

250 ml. of dioxane.

The suspension is added drop by drop to a suspension of

7 g. of lithium aluminum hydride in

500 ml. of ether.

Thereafter the reaction mixture is boiled under reflux for one hour.After decomposing the lithium aluminum hydride complex compound, theethereal solution is separated, the ether is distilled off, and theresidue is recrystallized from isopropanol. Melting point: 54°-55° C.Yield: 25 g.

c. 25 g. of the compound obtained as described hereinabove under (b),

9 g. of diethylamino ethylchloride,

15 ml. of triethylamine, and

150 ml. of methyl ethyl ketone

are boiled under reflux for 10 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The filtrate isevaporated by distillation to dryness and the residue is dissolved inbenzene. The benzene solution is washed with 20% sodium hydroxidesolution. The washed benzene layer is separated and extracted with 150ml. of N hydrochloric acid. The base is set free from said hydrochloricacid extract by the addition of ammonia. It is extracted therefrom withbenzene. The benzene solution is dried and the solvent is distilled off.The residue is dissolved in 100 ml. of acetone. 5 g. of fumaric acid areadded to said solution which is heated to boiling on the water bath.Small amounts of insoluble matter are filtered off and the solution iscooled. The precipitated fumarate is recrystallized from 96% ethanol.Melting point: 152°-154° C. Yield: 22 g.

EXAMPLE 42 1-(o-benzyloxy-benzyl)- 2-phenyl-4-diethylamino ethylpiperazine ##STR44##

a. 38 g. of 2-phenyl-3-keto piperazine,

52 g. of o-benzyloxy benzylchloride,

50 ml. of triethylamine, and

400 ml. of methyl ethyl ketone

are boiled under reflux for four hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The methyl ethylketone is distilled off. The residue is dissolved in isopropanol andwater is added thereto, while heating, until crystallization sets in.Melting point: 159°-160° C. Yield: 50 g.

b. 39 g. of the compound prepared as described hereinabove under (a) aredissolved in

100 ml. of anhydrous dioxane.

The solution is added drop by drop to a suspension of

10 g. of lithium aluminum hydride in 900 ml. of absolute ether.Thereafter the mixture is boiled under reflux for one and a half hours.The resulting lithium aluminum hydride complex compound is decomposed bya treatment with 10 ml. of 15% sodium hydroxide solution followed by atreatment with 10 ml. of water, 30 ml. of 15% sodium hydroxide solution,and finally 20 ml. of water. The solution is filtered. The solvent isdistilled off. The residue is dissolved in benzene and the benzenesolution is extracted with 300 ml. of N/2 hydrochloric acid. Thehydrochloric acid extract is rendered strongly alkaline by the additionof ammonia. The precipitated base is extracted with benzene. The benzenesolution is dried and the benzene is distilled off. The remaining baseis distilled in a vacuum. Boiling point: 205° C./0.03 mm. The base isthen recrystallized twice from n-heptane. Melting point: 82°-85° C.Yield: 35 g.

c. 30 g. of the compound prepared as described hereinabove under (b),

12.5 g. of diethylamino ethylchloride,

30 ml. of triethylamine, and

150 ml. of methyl ethyl ketone

are boiled under reflux for 12 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The solvent isdistilled off from the filtrate. The residue is dissolved in benzene.The benzene solution is extracted with 300 ml. of N hydrochloric acid.The base is precipitated from the hydrochloric acid extract by theaddition of ammonia. The precipitated base is then extracted withbenzene. The benzene solution is dried by means of potassium carbonateand the solvent is distilled off. The residue is distilled in a vacuum.Boiling point: 230°-235° C./0.03 mm. Yield: 25 g.

EXAMPLE 43 1-(p-Methoxy benzyl)-2-phenyl-4-diethylamino propylpiperazine ##STR45##

28 g. of 1-(p-methoxy benzyl)-2-phenyl piperazine obtained as describedhereinabove in Example 3 (b),

20 g. of diethylamino propylchloride,

50 ml. of triethylamine, and

200 ml. of methyl ethyl ketone

are boiled under reflux for 12 hours. Precipitated triethylaminehydrochloride is filtered off. The solvent is removed by distillation.The residue is dissolved in benzene. The benzene solution is extractedwith an acetic acid-water mixture 1 : 7). The acetic acid solution isseparated from the benzene solution and is rendered alkaline by theaddition of ammonia. The precipitated oily base is extracted in benzene,dried by means of potassium carbonate, and the benzene is distilled off.The remaining base is distilled in a vacuum. Boiling point: 200° C./0.01mm.

The crude base is dissolved in 100 ml. of absolute ethanol and thesolution is acidified by the addition of absolute alcoholic hydrochloricacid to a pH of 1.0. The precipitated hydrochloride is filtered off bysuction and dried. The salt starts to sublimate at 200° C. and melts at228°-231° C. with decomposition. The hydrochloride is dissolved inwater. The base is set free by the addition of ammonia and is extractedwith benzene. The benzene is distilled off from the benzene solution.The remaining base is again distilled in a vacuum. Boiling point: 210°C./0.02 mm. Colorless oil. Yield: 21 g.

EXAMPLE 44 1-(3-Chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine##STR46##

a. 17.5 g. of 1-(3-chloro benzyl)-2-phenyl-3-keto piperazine obtained asdescribed in Example 44 (a) of Application Ser. No. 333,497

are suspended in 50 ml. of absolute dioxane. The suspension is addeddrop by drop, while stirring, to a suspension of

4.5 g. of lithium aluminum hydride in

400 ml. of absolute ether.

Thereafter, the reaction mixture is boiled under reflux for one and ahalf hours. The resulting complex compound is decomposed by a treatmentfirst with

4.5 ml. of 15% sodium hydroxide followed by a treatment with 4.5 ml. ofwater,

14.5 ml. of 15% sodium hydroxide solution, and finally 9.0 ml. of water.

The hydroxide precipitate is filtered off and the solvent is distilledoff from the filtrate. The residue is dissolved in 20 ml. of N aceticacid. After allowing the solution to stand for 24 hours, the solidprecipitate is filtered off. The filtrate is rendered alkaline by theaddition of ammonia and the precipitated base is extracted with benzene.After drying the benzene solution, the solvent is distilled off. Theresidue is dissolved in 30 ml. of absolute ethanol and is adjusted to apH of 1.0 by the addition of absolute alcoholic hydrochloric acid. Theprecipitated hydrochloride is filtered off by suction and dried. Meltingpoint: 239°-242° C. The hydrochloride is dissolved in water. The base isset free by the addition of ammonia and is extracted with benzene. Afterdrying the benzene solution and distilling off the benzene, the oilyresidue is distilled in a vacuum. Boiling point: 145° C./0.05 mm.Colorless oil.

b. 10 g. of the base obtained as described hereinabove under (a),

150 ml. of acetone,

9.0 g. of diethylamino ethylchloride, and

10 ml. of triethylamine

are boiled under reflux for 14 hours. The reaction mixture is cooled andthe precipitated triethylamine hydrochloride is filtered off by suction.The filtrate is evaporated to dryness. The residue is dissolved inbenzene. The benzene solution is extracted with 100 ml. of Nhydrochloric acid. The hydrochloric acid extract is rendered alkaline.The precipitated base is extracted with benzene. The benzene solution isthen dried by means of potassium carbonate and the benzene is distilledoff. The remaining residue is distilled in a vacuum. Boiling point: 170°C./0.07 mm. Yellowish, mobile oil. Yield: 12 g.

EXAMPLE 45 1-(2-Chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine##STR47##

a. 51 g. of 1-(2-chloro benzyl)-2-phenyl-3-keto piperazine prepared asdescribed in Example 46 (a) of Application Serial No. 333,497 aresuspended in

100 ml. of dioxane.

The suspension is added to a suspension of

11 g. of lithium aluminum hydride in

700 ml. of absolute ether and

50 ml. of dioxane,

while stirring. Thereafter, the reaction mixture is boiled under refluxfor one and a half hours. The resulting complex compound is decomposedfirst by a treatment with

11 ml. of 15% sodium hydroxide solution followed by a treatment with

11 ml. of water,

33 ml. of 15% sodium hydroxide solution, and finally with

22 ml. of water.

After filtering off by suction the hydroxide precipitate, the solvent isdistilled off from the filtrate. The residue is dissolved in 100 ml. ofabsolute ethanol and 35 ml. of alcoholic hydrochloric acid (about 8 N)are added thereto. The precipitated hydrochloride is filtered off bysuction, washed, and dried. Melting point: 276°-277° C. Thehydrochloride is dissolved in water. The base is set free therefrom bythe addition of ammonia and is extracted with benzene. The benzenesolution is dried and the solvent is distilled off. The remaining baseis distilled in a vacuum. Boiling point: 136° C./0.08 mm. Yield: 38 g.

b. 10 g. of the base obtained as described hereinabove under (a),

150 ml. of acetone,

9 g. of diethylamino ethylchloride, and

10 ml. of triethylamine

are boiled under reflux for 14 hours. The reaction mixture is cooled andthe precipitated triethylamine hydrochloride is filtered off by suction.The filtrate is then evaporated to dryness. The residue is dissolved inwater and is extracted with benzene. The benzene solution is separatedfrom the aqueous phase and is extracted with 50 ml. of N hydrochloricacid. The hydrochloric acid extract is rendered alkaline by the additionof ammonia and the base set free thereby is extracted with benzene. Thebenzene solution is dried by means of potassium carbonate and thesolvent is distilled off. The residue is distilled in a vacuum. Boilingpoint: 160° C./0.05 mm. Yield: 11.5 g.

EXAMPLE 46 1-(3-Trifluoromethyl benzyl)-2-phenyl-4-diethylamino ethylpiperazine ##STR48##

a. 60 g. of 1-(3-trifluoromethyl benzyl)-2-phenyl-3-keto piperazineprepared as described in Example 51 (a) of Application Serial No.333,497 are dissolved in

120 ml. of dioxane.

The solution is added drop by drop to a suspension of

14 g. of lithium aluminum hydride in

700 ml. of absolute ether and

50 ml. of dioxane,

while stirring. Thereafter, the reaction mixture is boiled under refluxfor two hours. The resulting complex compound is decomposed first by atreatment with

14 ml. of 15% sodium hydroxide solution followed by a treatment with

14 ml. of water,

42 ml. of 15% sodium hydroxide solution, and finally

28 ml. of water.

The hydroxide precipitate is filtered off and the solvent is distilledoff from the filtrate. The residue is dissolved in 200 ml. of absoluteethanol and 35 ml. of an absolute alcoholic solution of hydrochloricacid (8 N) added thereto. The precipitated hydrochloride is filtered offby suction. It is washed with a mixture of acetic acid ethyl ester andalcohol (1 : 1) and is dried. The resulting hydrochloride is dissolvedin a small amount of water. The base is set free from said solution bythe addition of ammonia and is extracted with benzene. The benzenesolution is dried and the solvent is distilled off. The remaining baseis distilled in a vacuum. Boiling point: 120° C./0.05 mm. Yield: 40 g.

b. 10 g. of the base obtained as described hereinabove under (a),

150 ml. of acetone,

9 g. of diethylamino ethylchloride, and

10 ml. of triethylamine

are boiled under reflux for 14 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The solvent isdistilled off from the filtrate. The residue is dissolved in benzene.The benzene solution is washed once with water and is then extractedwith 50 ml. of N hydrochloric acid. The hydrochloric acid extract isrendered alkaline by the addition of ammonia. The base set free therebywhich forms the upper layer is extracted with benzene. The benzenesolution is dried and the solvent is distilled off. The remaining baseis distilled in a vacuum. Boiling point: 147° C./0.05 mm. Yellowish,mobile oil. Yield: 12.5 g.

EXAMPLE 47 1-(p-Chloro benzyl)-2-phenyl-4-piperazino ethyl piperazine##STR49##

5 g. of 1-(p-chloro benzyl)-2-phenyl-4-[(3-keto)piperazino ethyl]piperazine obtained as described hereinabove in Example 23 are dissolvedin

100 ml. of absolute dioxane.

The solution is added drop by drop to a suspension of 5 g. of lithiumaluminum hydride in 500 ml. of absolute ether. After addition iscompleted, the reaction mixture is boiled under reflux for two hours.The resulting complex compound is then decomposed first by the additionof

5 ml. of 15% sodium hydroxide solution followed by the addition of

5 ml. of water,

5 ml. of 15% sodium hydroxide solution, and finally

10 ml. of water.

The inorganic hydroxides are filtered off from the reaction mixture andthe solvent is distilled off. The residue is dissolved in benzene. Thebenzene solution is extracted with dilute acetic acid (1 : 10). Ammoniais added to the acetic acid solution. The precipitated base is extractedwith benzene. The benzene solution is dried and the benzene is distilledoff. The remaining base is distilled in a vacuum. Boiling point: 190°C./0.05 mm. Very viscous yellow oil. Yield: 3 g.

EXAMPLE 48 1-(p-Methoxy benzyl)-2-phenyl-4-piperidino ethyl piperazine##STR50##

13 g. of 1-(p-methoxy benzyl)-2-phenyl piperazine obtained as describedhereinabove in Example 4 (b),

10 g. of piperidino ethylchloride,

40 cc. of triethylamine, and

100 cc. of methyl ethyl ketone

are boiled under reflux for 18 hours. Without separating theprecipitated triethylamine hydrochloride the solvent is distilled off.The residue is dissolved in benzene and water. The aqueous phase isseparated and the benzene solution is extracted with dilute acetic acid(1 : 6). The acetic acid solution is then precipitated by the additionof ammonia. The precipitated base is extracted with benzene, dried bymeans of potassium carbonate, and the benzene is distilled off. The baseis distilled in a vacuum. Boiling point: 210° C./0.001 mm. Light yellow,viscous oil. Yield: 15 g.

EXAMPLE 49 4-Diethylamino ethyl-3-phenyl-(3,4,5-trimethoxy benzyl)piperazine ##STR51##

20 g. of 1-diethylamino ethyl-2-phenyl piperazine prepared as describedhereinabove in Example 8 (b),

17 g. of 3,4,5-trimethoxy benzylchloride,

250 ml. of acetone, and

20 ml. of triethylamine

are boiled under reflux for 8 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The acetone isdistilled off in a vacuum. The residue is dissolved in benzene, and thebenzene solution is extracted with 50 ml. of N hydrochloric acid. Thehydrochloric acid extract is rendered alkaline by the addition ofammonia. The precipitated base is extracted with benzene. After dryingby means of potassium carbonate, the solvent is distilled off. Theremaining base is distilled in a vacuum. Boiling point: 210° C./0.05 mm.Yellowish, viscous oil. Yield: 19 g.

EXAMPLE 50 4-Diethylamino ethyl-3-phenyl-1-(p-chloro phenyl ethyl)piperazine ##STR52##

20 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as describedhereinabove in Example 8 (b),

17 g. of p-chloro phenyl ethylchloride,

20 ml. of triethylamine, and

100 ml. of dimethylformamide

are heated on the water bath for 12 hours. The dimethylformamide is thendistilled off in a vacuum. The residue is dissolved in acetone. Theprecipitated triethylamine hydrochloride is filtered off by suction andthe acetone is distilled off from the filtrate. The resulting base isdissolved in benzene and extracted with 50 ml. of N hydrochloric acid.The hydrochloric acid extract is precipitated by the addition ofammonia. The precipitated base is extracted with benzene. The benzenesolution is dried by means of potassium carbonate and the benzene isdistilled off therefrom. The remaining base is distilled in a vacuum.Boiling point: 190° C./0.02 mm. Yield: 13 g.

EXAMPLE 51 4-Diethylamino ethyl-3-phenyl-1-(o-benzyloxy benzyl)piperazine ##STR53##

27 g. of 1-diethylamino ethyl-2-phenyl piperazine prepared as describedhereinabove in Example 8 (b),

27 g. of 2-benzyloxy benzyl chloride,

25 ml. of triethylamine, and

250 ml. of acetone

are boiled under reflux for 4 hours. The precipitated triethylaminehydrochloride is filtered off by suction. The acetone is removed bydistillation. The residue is dissolved in benzene and water. The benzenesolution is separated from the aqueous phase and is extracted with 100ml. of 0.5 N hydrochloric acid. The hydrochloric acid extract isrendered alkaline by the addition of ammonia and the precipitated baseis extracted with benzene. After drying the benzene extract, the solventis distilled off. Boiling point: 232° C./0.03 mm. Yellowish oil. Yield:26 g.

EXAMPLE 52 4-Diethylamino ethyl-3-phenyl-1-(p-benzyloxy benzyl)piperazine ##STR54##

30 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as describedhereinabove in Example 8 (b),

100 ml. of methyl ethyl ketone,

50 ml. of triethylamine, and

24 g. of p-benzyloxy benzylchloride

are boiled under reflux for 12 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The methyl ethylketone is distilled off from the filtrate. The residue is dissolved inbenzene and water. The benzene solution is separated from the aqueousphase and is extracted with 250 ml. of 0.1 N hydrochloric acid. Thehydrochloric acid extract is rendered alkaline by the addition ofammonia. The precipitated base is extracted with benzene. The benzenesolution is dried and the solvent is distilled off. Boiling point of theremaining base: 245° C./0.005 mm. Yellow, very viscous oil. The base isdissolved in a small amount of ethanol and its hydrochloride isprecipitated from the solution by the addition of absolute alcoholichydrochloric acid. The hydrochloride is filtered off by suction and isdried. The hydrochloride is dissolved in water. The base is set free bythe addition of ammonia, extracted with benzene, dried, and the solventis distilled off. The residue is recrystallized from petroleum ether.Melting point: 58° C. Yield: 33 g.

EXAMPLE 53 4-Diethylamino ethyl-3-phenyl-1-(p-hydroxy benzyl) piperazine##STR55## 25 g. of 1-diethylamino ethyl-3-phenyl-4-(p-benzyloxy benzyl)piperazine obtained as described hereinabove in Example 52 are dissolvedin 500 ml. of toluene. 4 g. of palladium asbestos are added thereto andhydrogen is introduced into the solution at room temperature under apositive pressure of 50 mm. Hg. A white, crystalline compound starts toprecipitate on the catalyst after 15 hours. Introduction of hydrogen isdiscontinued. The catalyst is filtered off by suction and is washed with500 ml. of 60° C. toluene. The toluene is distilled off and theremaining residue is recrystallized first from n-heptane andsubsequently from isopropanol. Melting point: 144° C. Yield: 11 g.EXAMPLE 54 4-Diethylamino ethyl-3-phenyl-1-benzyl piperazine ##STR56##

15 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as describedhereinabove in Example 8 (b),

8 g. of benzylchloride,

150 ml. of methyl ethyl ketone, and

20 ml. of triethylamine

are boiled under reflux for 8 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The acetone isdistilled off and the residue is dissolved in benzene. The benzenesolution is extracted with 100 ml. of N-hydrochloric acid. Thehydrochloric acid extract is rendered alkaline by the addition ofammonia. The precipitated base is extracted with benzene. The benzenesolution is dried and the solvent is distilled off therefrom. Theresidue is distilled in a vacuum. Boiling point: 160° C./0.01 mm.Yellowish oil. Yield: 10 g.

EXAMPLE 55 4-Diethylamino ethyl-3-phenyl-1-(3,4-dibenzyloxy benzyl)piperazine hydrochloride ##STR57##

23 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as describedhereinabove in Example 8 (b),

30 g. of 3,4-dibenzyloxy benzylchloride,

20 ml. of triethylamine, and

200 ml. of methyl ethyl ketone

are boiled for 12 hours under reflux. The precipitated triethylaminehydrochloride is filtered off by suction. The solvent is distilled off.The residue is dissolved in benzene. The benzene solution is extractedwith 100 ml. of N hydrochloric acid. The hydrochloric acid extract isprecipitated by the addition of ammonia. The precipitated base isdissolved in benzene, the benzene solution is dried and the solvent isdistilled off. Absolute alcoholic hydrochloric acid is added to theresidue in an amount to yield a pH of 1.0 and a mixture of petroleumether and acetone (1:1) is slowly added thereto. The hydrochlorideprecipitates and is filtered off by suction. It is dissolved in alcoholand is again precipitated by careful addition of a mixture of petroleumether and acetone (1:1).

The compound obtained after filtering and drying starts to sublimate at203° C. and has a melting point of 235°-239° C. with decomposition.Yield: 39 g.

EXAMPLE 56 4-Diethylamino ethyl-3-phenyl-1-(p-methoxy benzyl) piperazine##STR58##

64 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as describedhereinabove in Example 8 (b),

39 g. of p-methoxy benzylchloride,

75 g. of triethylamine, and

500 ml. of acetone

are boiled under reflux for 7 hours. After cooling, the precipitatedtriethylamine hydrochloride is filtered off by suction. The filtrate isevaporated to dryness. The residue is dissolved in benzene and isextracted with 200 ml. of N hydrochloric acid. Ammonia is added to thehydrochloric acid extract and the precipitated base is extracted withbenzene. The benzene solution is dried by means of potassium carbonateand the solvent is distilled off. The residue is distilled in a vacuum.Boiling point: 180°-182° C./0.005 mm. Yellowish oil. Yield: 24 g.

The new 1,4-substituted phenyl piperazine compounds to the presentinvention and their pharmaceutically acceptable acid addition salts canbe administered orally, parenterally, or rectally. Compositionscontaining said compounds as used in therapy, comprise, for instance,tablets, pills, dragees, lozenges, and the like shaped preparations tobe administered orally. Said compounds may also be administered inpowder form, preferably enclosed in gelatin or the like capsules. Oraladministration in liquid form, such as in the form of solutions,emulsions, suspensions, sirups, and the like is also possible. Suchsolid or liquid preparations are produced in a manner known to the artof compounding and processing pharmaceutical compositions whereby theconventional diluting, binding, and/or expanding agents, lubricants,and/or other excipients, such as lactose, cane sugar, dextrins, starch,talc, kaolin, magnesium hydroxide, magnesium carbonate, pectin, gelatin,agar, bentonite, stearic acid, magnesium stearate, and others may beemployed.

The following examples serve to illustrate the preparation ofpharmaceutical compositions as they are used in therapy without,however, limiting the same thereto.

EXAMPLE 57

Tablets:

20 g. of the dihydrochloride of 1-(4'-chlorobenzyl)-2-phenyl-4-diethylamino ethyl piperazine, 128 g. of lactose, and2 g. of magnesium stearate are intimately mixed with each other and arecompressed without preceding granulation to tablets weighing 150 mg.Each tablet contains 20 mg. of the anticoagulant agent according to thepresent invention.

EXAMPLE 58

The mixture of ingredients as given in Example 57 is compressed tobiconvex dragee cores of 150 mg. each. These cores are repeatedlysugar-coated by rotating in a coating pan with sugar sirup. Each drageecontains 20 mg.

EXAMPLE 59

Capsules:

500 g. of 1-(3',4'-dichloro benzyl)-2-phenyl-4-diethylamino ethylpiperazine dihydrochloride are intimately mixed with 200 g. of starchand the mixture is sieved. Portions of 700 mg. each of said mixture arefilled in gelatin capsules. Each capsule contains 500 mg. of theanticoagulant agent.

EXAMPLE 60

Suppositories:

400 g. of the molten suppository base Adeps solidus and 10 g. of thesuccinate of 1-(4'-chloro benzyl)-2-phenyl-4-piperidino ethyl piperazineare thoroughly triturated while maintaining in the molten state. Themolten mixture is cast into suppository molds, each of which contains2.05 g. of the mixture. The molds are then cooled to causesolidification. Each suppository contains 50 mg. of the anticoagulantagent.

EXAMPLE 61

25 mg. of 1-(4'-chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazinedihydrochloride are dissolved in 2.2 cc. of bidistilled water. Thissolution is filled in ampoules which are sterilized in an autoclave at120° C.

Ampoules containing 5 mg. to 250 mg. of base may be prepared as follows:The base is dissolved in water by the addition of a stoichiometricallyequivalent amount of the desired acid. As an acid, there may be usede.g. hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid,succinic acid, fumaric acid, lactic acid, and the like.

The effect which 1,4-disubstituted phenyl piperazine compounds accordingto the present invention have on blood coagulation, was determinedaccording to standard test methods in vitro with human blood. Theresults of such tests are given in the following Table. The test mixturewas prepared by adding one part of the aqueous solution of the compoundto be tested to 9 parts of plasma. The compound to be tested was used inthe form of its hydrochloride. Thus 0.1 millimole (mM) as given in theTable indicates 9 ml. of plasma plus 1 ml. of a millimolar (mM) aqueoussolution of the compound to be tested.

The effect of the compounds according to the present invention wasdetermined by measuring the recalcification time as well as the stypventime.

The determination of the recalcification time is based on the fact thatfree calcium⁺ ⁺ ions are required to cause coagulation. Because thecalcium ions are bound in the blood which has been renderednon-coagulable by the addition of citrate or oxalate, excess calciumchloride solution is added in this test and the period of timecalculated from the additon of the calcium chloride to the onset ofcoagulation is measured. This period of time is the recalcificationtime.

For determining the stypven time, there is added, in addition to thecalcium ions, the viper poison stypven to the citrate or oxalate blood.The stypven test is an especially sensitive test for detecting lipidesset free from the thrombocytes.

In order to determine the effect of the compounds according to thepresent invention upon thrombocytes which are principal features withrespect to coagulation of blood, the recalcification time and thestypven time were determined in blood rich in thrombocytes as well as inblood poor in thrombocytes.

It is assumed that the formation of blood clots is initiated bythrombocyte aggregation. Therefore, the compounds according to thisinvention were also tested for their thrombocyte aggregation, inhibitingeffect by the method described by Klaus Breddin in "SchweizerischeMedizinische Wochenschrift" vol. 20, p. 655 (1965).

The following Table shows those concentrations of the tested compounds,determined by means of their recalcification time and their stypventime, which indicate a pronounced blood coagulation promoting effect aswell as a pronounced blood coagulation inhibiting effect. Theseconcentrations are given in millimoles of the respective compound. Theconcentrations at which inhibition of the thrombocyte aggregation setsin, are also given for some of the compounds. That one and the samecompound can have a blood coagulation promoting as well as a bloodcoagulation inhibiting effect, is due to the fact that it acts uponvarious coagulation factors at the same time. Thus a compound is able toset free from the thrombocytes coagulation activating material at a lowconcentration while at a higher concentration certain coagulationfactors have an inhibiting effect.

o in said Table indicates that no effect has been found within thetested concentration range.

The recalcification time was determined according to the method of E.DEUTSCH ET AL. in "Thrombosis et Diathesis Haemorrhagica" vol. XXVI,page 145(1971) and the stypven time according to the method of McKENZIEET AL. in "Amer. Journ. Clin. Path." vol. 55, pages 551-554.

It has also been found that a number of the compounds according to thepresent invention possess fibrinolytic activity, i.e. they are capableof dissolving thrombi which have been formed.

                                      TABLE                                       __________________________________________________________________________                               Coagulation promoting                                                                       Coagulation inhibiting                                                                      Inhibition of                                     effect        effect        thrombocytes                                      Plasma rich                                                                          Plasma poor                                                                          Plasma rich                                                                          Plasma poor                                                                          aggregation            Exam-                      in     in     in     in     according to           ple                  Molecular                                                                           thrombocytes  thrombocytes  Breddin                No. Compound         weight                                                                              mM     mM     mM     mM     mM                     __________________________________________________________________________        1-(4-Chloro benzyl)-2-                                                        phenyl-4-diethylamino-                                                        ethyl-3-keto-piperazine                                                                        399.9 1      1      55     5      0.1                    1   4-Diethylaminoethyl-2-                                                        phenyl-1-(4-chloro benzyl)                                                    piperazine       386.0 1      1      5      5      1                      2   1-(3,4-Dichloro benzyl)-2-                                                    phenyl-4-diethylaminoethyl-                                                   piperazine       420.4 0.1 - 1                                                                              1      2.5    2.5    0.1                    3   1-(p-Methoxyphenyl-ethyl)-                                                    2-phenyl-4-Methylamino                                                        ethyl piperazine 395.5 1      1      10     5      0.1-0.5                4   1-(3-Phenylpropyl)-2-                                                         phenyl-4-diethylamino-                                                        ethyl piperazine 379.5 0.1 - 1                                                                              1      5      2.5    0.1-0.5                5   1-(4-Chloro benzyl)-2-                                                        phenyl-4-(2-piperidino                                                        ethyl) piperazine                                                                              397.9 1      1      5      2.5-5  0.1                    5   1-(p-chloro benzyl)-2-                                                        phenyl-4-[(4-methyl)-pip-                                                     erazine ethyl-(1)]piper-                                                      azine            413.01                                                                              0.1    0.1    2.5    2.5    0.1                    5   1-(p-Chloro benzyl)-2-phenyl-                                                 4-pyrrolidino ethyl pipera-                                                   zine             383.97                                                                              0.1    1      5      2.5    0.5                    6   1-(4-Chloro benzyl)-2-phenyl-                                                 4-(1,3-bis-(morpholino propyl)                                                piperazine       499.08                                                                              1      1      5      2.5    0.1-1                  7   1-(p-Chloro benzyl)-3-phenyl-                                                 4-diethylamino ethyl piper-                                                   azine            386.1 0.1    1      5      2.5    0.01-0.1               8   4-Diethylaminoethyl-3-phenyl-                                                 1-(p-ethoxy benzyl)piperazine                                                                  395.6 0.1-1  1      5      1-2.5  0.01-0.1                   4-Diethylaminoethyl-3-phenyl-                                                 2-keto-1-(p-chloro benzyl)                                                    piperazine       399.95                                                                              1      1      5      2.5-5  0.1                    14  4-Dimethylaminoethyl-2-phenyl-                                                1-(3,4-dichloro benzyl)-pip-                                                  erazine          392,38                                                                              0.1    1      2.5    2.5    0.1-0.5                15  4-β-Morpholinoethyl-2-phenyl-                                            (3,4-dichloro benzyl)pipera-                                                  zine             434.42                                                                              1      1      --     --     0.1                    16  4-Diethylaminopropyl-2-phen-                                                  yl-1-(3,4-dichloro benzyl)                                                    piperazine       434,462                                                                             0.1    1      2.5    2.5    0.01                   17  1-(4-Benzyloxy benzyl)-2-                                                     phenyl-4-diethylaminoethyl                                                    piperazine       457,66                                                                              0.1    0.1    2.5    2.5                           18  4-Diethylaminoethyl-2-phen-                                                   yl-1-(3,4,5-trimethoxy ben-                                                   zyl) piperazine  4.41.596. 1                                                                         --     --     5      0.1                           19  1-[(p-Methoxy phenyl propyl)]-                                                2-phenyl-4-diethylaminoethyl                                                  piperazine       409,626                                                                             0.1    1      5      5      0.1-0.5                20  4-Diethylaminoethyl-3-phenyl-                                                 1-(p-ethoxy benzyl)pipera-                                                    zine             395,6 0.1-1  1      5      1 - 2.5                                                                              0.1-0.5                22  1-(p-Chloro benzyl-2-phen-                                                    yl-4-[(4-methyl)piperazino                                                    ethyl-(1)]piperazine                                                                           413.01                                                                              0.1    0.1    5      2.5                           23  1-(p-Chlorobenzyl)-2-phenyl-                                                  4-[3-keto)-piperazinoethyl)-                                                  (1)] piperazine  466.99                                                                              0.1    0.5    o      o                             5a  1-(p-Chloro benzyl)-2-                                                        phenyl-4-pyrrolidino                                                          ethyl piperazine 383,97                                                                              1      o      5      2.5                           34  4-Diethylaminoethyl-3-                                                        phenyl-1-(o-hydroxy benzyl)                                                   piperazine       367.5 1      1      5      5      --                     36  4-Diethylaminoethyl-3-phen-                                                   yl-1-(3,4,5-trimethoxybenz-                                                   yl) piperazine   441.5 1      o      o      2.5    --                     37  1-(p-Hydroxy benzyl)-2-                                                       phenyl-4-diethylaminoethyl                                                    piperazine       367.5 1      1      o      o      --                         1-(p-Ethoxy benzyl)-2-phen-                                                   yl-4-pyrrolidinoethyl-3-                                                      keto piperazine  407,53                                                                              1      1      o      5                             47  1-(p-Chloro benzyl)-2-phen-                                                   yl-4-piperazino ethyl                                                         piperazine       399.0 0.1    0.1    2.5    5                             48  1-(p-Methoxy benzyl)-2-                                                       phenyl-4-piperidinoethyl                                                      piperazine       393.55                                                                              1      o      5      2.5                           49  4-Diethylaminoethyl-3-phen-                                                   yl-1-(3,4,5-trimethoxy)-                                                      benzyl piperazine                                                                              441,5 1      o      o      2.5                           50  4-Diethylaminoethyl-3-                                                        phenyl-1-(p-chloro phen-                                                      yl)ethyl piperazine                                                                            400.00                                                                              0.1    o      5      2.5    0.05                   51  4-Diethylamino ethyl-3-                                                       phenyl-1-(o-benzyloxy                                                         benzyl) piperazine                                                                             457.66                                                                              0.1    o      5      0.1                           52  4-Diethylaminoethyl-3-                                                        phenyl-1-(p-benzyloxy                                                         benzyl) piperazine                                                                             457.66                                                                              0.1    1      2.5    2.5    1                      53  4-Diethylaminoethyl-3-                                                        phenyl-1-(p-hydroxy                                                           benzyl)piperazine                                                                              367.5 0.1    o      10     5      --                     54  4-Diethylamino ethyl-3-                                                       phenyl-1-benzyl piper-                                                        azine            351.54                                                                              0.1    0.1    0      o                             55  4-Diethylaminoethyl-3-                                                        phenyl-1-(3,4-dibenzyl-                                                       oxy benzyl)piperazine . HC1                                                                    563.79                                                                              1      0.1    2.5    o                                 4-Diethylaminoethyl-3-                                                        phenyl-2-keto-1-(p-ben-                                                       zyloxy benzyl) pipera-                                                        zine             471.65                                                                              1      1      10     2.5                           40  1-(p-Chloro benzyl)-2-                                                        phenyl-4-dimethylamino                                                        propyl piperazine                                                                              371,94                                                                              0.01   0.1    2.5    2.5                           41  1-(3,4-Dibenzyloxy benzyl)-                                                   2-phenyl-diethylaminoethyl                                                    piperazine fumarate                                                                            563.79                                                                              1      1      2.5    2.5                           42  1-(o-Benzyloxy benzyl)-2-                                                     phenyl-4-diethylaminoethyl                                                    piperazine       457.66                                                                              0.1    1      5      2.5                           43  1-(p-Methoxybenzyl)-2-                                                        phenyl-4-diethylamino                                                         propyl piperazine                                                                              395,57                                                                              0.1    o      5      5                             __________________________________________________________________________

The starting materials are either commercially available or can besynthesized from commercially available compounds by known methods.

For instance, α-chloro phenyl acetic acid ethyl ester used as the onereactant in Example 1 B (a), is prepared from commercially availableα-chloro phenyl acetic acid chloride by esterifying with ethanol. Itsboiling point is 123°-125° C./8-10 mm.

N₁ -(diethylamino ethyl) ethylene diamine, the other reactant of Example1 B (a) is obtained according to the method of H. F. McKay "Canad. J.Chem." vol. 34, pp. 1567-1573 (1956).

1-(β-Chloro ethyl)-4-methyl piperazine used as reactant in Example 6, isprepared by reacting 1(β-hydroxy ethyl)-4-methyl piperazine andthionylchloride.

1,3-Dimorpholino propylchloride (Example 7) is obtained by reacting1,3-dimorpholino propanol with thionylchloride.

p-Ethoxy benzylchloride (Example 9 c) is produced according to Bergmannand Sulzbacher "J. org. Chem." vol. 16, p. 85 (1951).

3,4,5-Trimethoxy benzylchloride (Example 13) is prepared by reacting3,4,5-trimethoxy benzyl alcohol with thionylchloride and

3-(4'-Methoxy phenyl) propylchloride (1) by reacting 3-(4'-methoxyphenyl) propanol (1) with thionylchloride.

Acetyl glycolic acid chloride (Example 27 A c) is obtained according toGhosh "J. Indian Chem. Soc." vol. 24, p. 325 (1947) from acetyl glycolicacid synthesized according to Anschuetz et al. "Ber." vol. 30, p. 467.

1-(3,4-Dibenzyloxy benzyl)-2-phenyl-3-keto piperazine (Example 42 ) isobtained by reacting 2-phenyl-3-keto piperazine with 3,4-dibenzyloxybenzylchloride. Its melting point is 108°-110° C.

3,4-Dibenzyloxy benzylchloride (Example 43) is synthesized by firstproducing 3,4-dibenzyloxy benzaldehyde according to the method describedby Bergmann et al. "J. org. Chem." vol. 16, p. 85 (1951), reducing saidaldehyde with sodium boron hydride to the corresponding alcohol, andchlorinating the resulting alcohol with thionylchloride in chloroform.Melting point of the chloride: 42°-44° C.

o-Benzyloxy benzylchloride (Example 55) is obtained in an analogousmanner. Boiling point: 118° C./0.05 mm.

Diethylamino propylchloride (Example 56) is prepared by reactingdiethylamino propanol with thionylchloride.

p-Chloro phenyl ethylchloride (Example 63) is synthesized according toDepuy et al. "J. Am. Chem. Soc."vol. 79, pp. 3710-11 soc." (1957) andBaddeley et al. "J. Am. Chem. Soc." 1935, p. 1820.

p-Methoxy benzylchloride (Example 69) is prepared as described in "Org.Synth." vol. 36, p. 50.

The following example describes the preparation of a compound in whichR₄ and R₅ of Formulas VII to XII form an N₄ -hydroxy lower alkylpiperazine group.

EXAMPLE 62 1-(p-Chloro benzyl)-2-phenyl-4-[β-(4'-hydroxy ethylpiperazino) ethyl ] piperazine ##STR59##

The compound is obtained by reacting 1-(4'-chlorobenzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride asdescribed hereinabove in Example 21 B and C, with N₁ -(2-hydroxy ethyl)piperazine. The resulting reaction product is a yellow oil of theboiling point: 245° C./0.02 mm.

Analogous compounds in which the phenyl ring of the benzyl or phenyllower alkyl substituent in 1-position is substituted by othersubstituents than chloro, as well as compounds of the 3-phenylpiperazine type or the 2- or 3-phenyl-3- or -2-keto piperazine type andwhich have in 4-position a hydroxy lower alkyl piperazino lower alkylgroup can, of course, also be produced in a similar manner.

We claim:
 1. A 1,4-disubstituted phenyl piperazine compound of theformula ##STR60##in which X, Y, and Z are members selected from thegroup consisting of hydrogen, halogen, trifluoro lower alkyl, hydroxyl,lower alkoxy, and phenyl substituted lower alkoxy;R₁ is lower alkyl with1 to 3 carbon atoms; R₂ is lower alkyl; R₄ and R₅ are members selectedfrom the group consisting of lower alkyl, and, together with thenitrogen to which they are attached, form piperidino or pyrrolidino; andone of the groups A and B is the methylene group of the formula --CH₂--, while the other one of the groups A and B is the phenyl substitutedmethylene group of the formula ##STR61##or their pharmaceuticallyacceptable acid addition salts.
 2. A 1,4-disubstituted phenyl piperazinecompound of the formula ##STR62##in which X, Y, and Z are membersselected from the group consisting of hydrogen, halogen, trifluoro loweralkyl, hydroxyl, lower alkoxy, and phenyl substituted lower alkoxy;R₁ islower alkyl with 1 to 3 carbon atoms; R₂, r₄, and R₅ are lower alkyl;and one of the groups A and B is the methylene group of the formula--CH.sub. 2 --, while the other one of the groups A and B is the phenylsubstituted methylene group of the formula ##STR63##or theirpharmaceutically acceptable acid addition salts.
 3. The1,4-disubstituted phenyl piperazine compound of claim 2, said compoundbeing a 1-(phenyl lower alkyl)-3-phenyl-4-(di-lower alkylamino loweralkyl) piperazine or its pharmaceutically acceptable acid additionsalts.
 4. The 1,4-disubstituted phenyl piperazine compound of claim 2,said compound being a 1-(phenyl lower alkyl)-3-phenyl-4-(di-loweralkylamino lower alkyl) piperazine, the phenyl ring in 1-position beingsubstituted by halogen, or its pharmaceutically acceptable acid additionsalts.
 5. The 1,4-disubstituted phenyl piperazine compound of claim 2,said compound being a 1-(phenyl lower alkyl)-3-phenyl-4-(di-loweralkylamino lower alkyl) piperazine, the phenyl ring in 1-position beingsubstituted by lower alkoxy, or its pharmaceutically acceptable acidaddition salts.
 6. The 1,4-disubstituted phenyl piperazine compound ofclaim 2, said compound being a 1-(phenyl loweralkyl)-2-phenyl-4-(di-lower alkylamino lower alkyl) piperazine or itspharmaceutically acceptable acid addition salts.
 7. The1,4-disubstituted phenyl piperazine compound of claim 2, said compoundbeing a 1-(phenyl lower alkyl)-2-phenyl-4-(di-lower alkylamino loweralkyl) piperazine, the phenyl ring in 1-position being substituted byhalogen, or its pharmaceutically acceptable acid addition salts.
 8. The1,4-disubstituted phenyl piperazine compound of claim 2, said compoundbeing a 1-(phenyl lower alkyl)-2-phenyl-4-(di-lower alkylamino loweralkyl) piperazine, the phenyl ring in 1-position being substituted bylower alkoxy, or its pharmaceutically acceptable acid addition salts. 9.The 1,4-disubstituted phenyl piperazine compound of claim 2, saidcompound being 1-(4'-chloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine, or its pharmaceutically acceptable acid addition salts. 10.The 1,4-disubstituted phenyl piperazine compound of claim 2, saidcompound being 1-(3',4'-dichlorobenzyl)-2-phenyl-4-(diethylamino ethyl)piperazine, or its pharmaceutically acceptable acid addition salts. 11.The 1,4-disubstituted phenyl piperazine compound of claim 1, saidcompound being 1-(4'-chloro benzyl)-2-phenyl-4-(piperidino ethyl)piperazine, or its pharmaceutically acceptable acid addition salts. 12.The 1,4-disubstituted phenyl piperazine compound of claim 2, saidcompound being 1-(4'-chloro benzyl)-3-phenyl-4-(diethylamino ethyl)piperazine, or its pharmaceutically acceptable acid addition salts. 13.The 1,4-disubstituted phenyl piperazine compound of claim 2, saidcompound being 1-[3'-phenyl propyl(1)]-2-phenyl-4-(diethylamino ethyl)piperazine, or its pharmaceutically acceptable acid addition salts. 14.The 1,4-disubstituted phenyl piperazine compound of claim 2, saidcompound being 1-[(4'-methoxy phenyl)ethyl]-2-phenyl-4-(diethylaminoethyl) piperazine, or its pharmaceutically acceptable acid additionsalts.